1-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

ABSTRACT

The present invention relates to 1-aza-dibenzoazulene derivatives, to their pharmacologically acceptable salts and solvates, to processes and intermediates for the preparation thereof as well as to their antiinflammatory effects, especially to the inhibition of tumour necrosis factor-α (TNF-α) production and the inhibition of interleukin-1 (IL-1) production as well as to their analgetic action.

This application is a National Stage under 35 U.S.C. §371 of PCTInternational Application No. PCT/HR03/00026, filed May 20, 2003, whichclaims the benefit under 35 U.S.C. §119(e) of prior Croatian ApplicationNo. P20020440A, filed May 21, 2002, the entire contents of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to 1-aza-dibenzoazulene derivatives, totheir pharmacologically acceptable salts and solvates, to processes andintermediates for the preparation thereof as well as to theirantiinflammatory effects, especially to the inhibition of tumournecrosis factor-α (TNF-α) production and the inhibition of interleukin-1(IL-1) production as well as to their analgetic action.

PRIOR ART

There are numerous literature data relating to various aza- anddiaza-dibenzoazulenes and to the preparation thereof. It is well-knownthat some compounds of such structure and salts thereof have anantiinflammatory action and represent a novel class of compounds havingsuch an action. Thus in a series of patents (U.S. Pat. No. 3,711,489,U.S. Pat. No. 3,781,294 and CA 967,573) the preparation ofdibenzoazulenes of imidazole class with various 2-substituents such astrifluoromethyl, pyridyl, naphthyl, phenyl and substituted phenyl isdisclosed. There were also prepared corresponding imidazole derivativeswith 2-alkylthio substituents of similar action (U.S. Pat. No.4,198,421; EP 372,445 and WO 9,118,885).

Dibenzoazulenes of pyrazole class having alkyl, phenyl or substitutedphenyl (FR 2,504,140; and Olivera R et al., Tetrahedron Lett., 2000,41:4353–4356 and 4357–4360) or acetyl and ethoxycarbonyl (Schulz H J etal., Z. Chem., 1988, 28:181–182) in 2-position are known as well.

There are also literature data disclosing the preparation of2-aza-dibenzoazulene derivatives such as N-methyl derivatives (Funke Cet al., Arzneim-Forsch., 1990, 40:536–539; Bennett R A et al., J.Heterocycl. Chem., 1994, 31:293–296) and several patents disclosingdihydro derivatives of 2-aza-dibenzoazulenes (U.S. Pat. No. 3,773,940;U.S. Pat. No. 3,859,439; U.S. Pat. No. 4,112,110; EP 125,484) andtetrahydro derivatives of 2-aza-dibenzoazulenes (U.S. Pat. No.4,271,179; EP 357,126 and WO 9,854,186). Further, also aromatic1-thia-dibenzoazulenes having aminoalkyloxy substituents on thiophenering, which also possess an antiinflammatory action (WO 01/87890) areknown.

According to our knowledge and to available literature data, completelyunsaturated aromatic 1-aza-dibenzoazulenes of the present invention havehitherto not been prepared or disclosed. Nor is it known that suchcompounds could possess an antiinflammatory action (inhibitors of TNF-αproduction, inhibitors of IL-1 production) or an analgetic action, saidactions also being an object of the present invention. In 1975 TNF-α wasdefined as a serum factor induced by endotoxin and causing tumournecrosis in vitro and in vivo (Carswell E A et al., Proc. Natl. Acad.Sci. U.S.A., 1975, 72:3666–3670). Besides an antitumour action, TNF-αalso possesses numerous other biological actions important in thehomeostasis of organisms and in pathophysiological conditions. The mainsources of TNF-α are monocytes-macrophages, T-lymphocytes andmastocytes.

The discovery that anti-TNF-α antibodies (cA2) are effective in treatingpatients with rheumatoid arthritis (RA) (Elliott M et al., Lancet, 1994,344:1105–1110) led to an increased interest in finding novel TNF-αinhibitors as possible potent drugs for RA. Rheumatoid arthritis is anautoimmune chronic inflammatory disease characterized by irreversiblepathological changes in the joints. In addition to RA, TNF-α antagonistsmay also be used in numerous pathological conditions and diseases suchas spondylitis, osteoarthritis, gout and other arthritic conditions,sepsis, septic shock, toxic shock syndrom, atopic dermatitis, contactdermatitis, psoriasis, glomerulonephritis, lupus erythematosus,scleroderma, asthma, cachexia, chronic obstructive lung disease,congestive cardiac arrest, insulin resistance, lung fibrosis, multiplesclerosis, Crohn's disease, ulcerative colitis, viral infections andAIDS.

Some of the proofs indicating the biological importance of TNF-α wereobtained by in vivo experiments in mice, in which mouse genes for TNF-αor its receptor were inactivated. Such animals are resistant tocollagen-induced arthritis (Mori L et al., J. Immunol., 1996,157:3178–3182) and to endotoxin-caused shock (Pfeffer K et al., Cell,1993, 73:457–467). In animal assays where the TNF-α level was increased,a chronic inflammatory polyarthritis occurred (Georgopoulos S et al., J.Inflamm., 1996, 46:86–97; Keffer J et al., EMBO J., 1991, 10:4025–4031)and its pathological picture was alleviated by inhibitors of TNF-αproduction. The treatment of such inflammatory and pathologicalconditions usually includes the application of non-steroidantiinflammatory drugs and, in more severe cases, gold salts,D-penicillinamine or methotrexate are administered. Said drugs actsymptomatically, but they do not stop the pathological process. Novelapproaches in the therapy of rheumatoid arthritis are based upon drugssuch as tenidap, leflunomide, cyclosporin, FK-506 and upon biomoleculesneutralizing the TNF-α action. At present there are commerciallyavailable etanercept (Enbrel, Immunex/Wyeth), a fusion protein of thesoluble TNF-α receptor, and infliximab (Remicade, Centocor), a chimericmonoclonal human and mouse antibody. Besides in RA therapy, etanerceptand infliximab are also registered for the therapy of Crohn's disease(Exp. Opin. Invest. Drugs, 2000, 9:103).

In an optimum RA therapy, besides inhibition of TNF-α secretion, alsothe inhibition of IL-1 secretion is very important since IL-1 is animportant cytokin in cell regulation and immunoregulation as well as inpathophysiological conditions such as inflammation (Dinarello C A etal., Rev. Infect. Disease, 1984, 6:51). Well-known biological activitiesof IL-1 are: activation of T-cells, induction of elevated temperature,stimulation of the secretion of prostaglandine or collagenase,chemotaxia of neutrophils and reduction of iron level in plasma(Dinarello C A, J. Clinical Immunology, 1985, 5:287). Two receptors towhich IL-1 may bind are well-known: IL-1RI and IL-1RII. Whereas IL-1RItransfers a signal intracellularly, IL-1RII is situated on the cellsurface and does not transfer a signal inside the cell. Since IL-1-RIIbinds IL-1 as well as IL-1-RI, it may act as a negative regulator ofIL-1 action. Besides this mechanism of signal transfer regulation incells, another natural antagonist of IL-1 receptor (IL-1ra) is presentin cells. This protein binds to IL-1RI but does not cause itsstimulation. Its potency in stopping the transfer of IL-1 stimulatedsignal is not high and its concentration has to be 500 times higher thanthat of IL-1 in order to achieve a break in the signal transfer.Recombinant human IL-1ra (Amgen) was clinically tested (Bresnihan B etal., Arthrit. Rheum., 1996, 39:73) and the obtained results indicated animprovement of the clinical picture over a placebo in RA patients. Theseresults indicate the importance of the inhibition of IL-1 action intreating diseases such as RA where IL-1 production is disturbed. Sincethere exists a synergistic action of TNF-α and IL-1, dual TNF-α and IL-1inhibitors may be used in treating conditions and diseases related to anenhanced secretion of TNF-α and IL-1.

Inventive Solution

The present invention relates to 1-aza-dibenzoazulene compounds of theformula I:

wherein

-   X may be CH₂ or a hetero atom such as O, S, S(═O), S(═O)₂, or    NR^(a), wherein R^(a) is hydrogen or a protecting group;-   Y and Z independently from each other denote hydrogen, one or more    identical or different substituents linked to any available carbon    atom, and may be halogen, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkinyl,    halo-C₁–C₄ alkyl, hydroxy, C₁–C₄ alkoxy, trifluoromethoxy, C₁–C₄    alkanoyl, amino, amino-C₁–C₄ alkyl, C₁–C₄ alkylamino,    N-(C₁–C₄-alkyl)amino, N,N-di(C₁–C₄-alkyl)amino, thiol, C₁–C₄    alkylthio, sulfonyl, C₁–C₄ alkylsulfonyl, sulfinyl, C₁–C₄    alkylsulfinyl, carboxy, C₁–C₄ alkoxycarbonyl, cyano, nitro;-   R¹ may be hydrogen, halogen, an optionally substituted C₁–C₇ alkyl    or C₂–C₇ alkenyl, C₂–C₇ alkinyl, an optionally substituted aryl or    heteroaryl and a heterocycle, hydroxy, hydroxy-C₂–C₇ alkenyl,    hydroxy-C₂–C₇ alkinyl, C₁–C₇ alkoxy, thiol, thio-C₂–C₇ alkenyl,    thio-C₂–C₇ alkinyl, C₁–C₇ alkylthio, amino, N-(C₁–C₇)alkylamino,    N,N-di(C₁–C₇-alkyl)amino, (C₁–C₇-alkyl)amino, amino-C₂–C₇ alkenyl,    amino-C₂–C₇ alkinyl, amino-C₁–C₇ alkoxy, C₁–C₇ alkanoyl, aroyl,    oxo-C₁–C₇ alkyl, C₁–C₇ alkanoyloxy, carboxy, an optionally    substituted C₁–C₇ alkyloxycarbonyl or aryloxycarbonyl, carbamoyl,    N-(C₁–C₇-alkyl)carbamoyl, N,N-di(C₁–C₇-alkyl)carbamoyl, cyano,    cyano-C₁–C₇ alkyl, sulfonyl, C₁–C₇ alkylsulfonyl, sulfinyl, C₁–C₇    alkylsulfinyl, nitro, or a substituent of the formula A:

wherein

-   R³ and R⁴ simultaneously or independently from each other may be    hydrogen, C₁–C₄ alkyl, aryl or together with N have the meaning of    an optionally substituted heterocycle or heteroaryl;-   m and n represent an integer from 0 to 3;-   Q₁ and Q₂ represent, independently from each other, oxygen, sulfur    or groups:

wherein the substituents

-   y₁ and y₂ independently from each other may be hydrogen, halogen, an    optionally substituted C₁–C₄ alkyl or aryl, hydroxy, C₁–C₄ alkoxy,    C₁–C₄ alkanoyl, thiol, C₁–C₄ alkylthio, sulfonyl, C₁–C₄    alkylsulfonyl, sulfinyl, C₁–C₄ alkylsulfinyl, cyano, nitro or    together form carbonyl or imino group;-   R² has the meaning of hydrogen, optionally substituted C₁–C₇ alkyl    or aryl or a protecting group: formyl, C₁–C₇ alkanoyl, C₁–C₇    alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl, C₁–C₇    alkylsilyl;-   as well as to pharmacologically acceptable salts and solvates    thereof.

The term “halo”, “hal” or “halogen” relates to a halogen atom which maybe fluorine, chlorine, bromine or iodine.

The term “alkyl” relates to alkyl groups with the meaning of alkaneswherefrom radicals are derived, which radicals may be straight, branchedor cyclic or a combination of straight and cyclic ones as well as ofbranched and cyclic ones. The preferred straight or branched alkyls aree.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.The preferred cyclic alkyls are e.g. cyclopentyl or cyclohexyl.

The term “haloalkyl” relates to alkyl groups which must be substitutedwith at least one halogen atom. The most frequent haloalkyls are e.g.chloromethyl, dichloromethyl, trifluoromethyl or 1,2-dichloropropyl.

The term “alkenyl” relates to alkenyl groups having the meaning ofhydrocarbon radicals, which may be straight, branched or cyclic or are acombination of straight and cyclic ones or branched and cyclic ones, buthaving at least one carbon-carbon double bond. The most frequentalkenyls are ethenyl, propenyl, butenyl or cyclohexenyl.

The term “alkinyl” relates to alkinyl groups having the meaning ofhydrocarbon radicals, which are straight or branched and contain atleast one and at most two carbon-carbon triple bonds. The most frequentalkinyls are e.g. ethinyl, propinyl or butinyl.

The term “alkoxy” relates to straight or branched chains of alkoxygroup. Examples of such groups are methoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy.

The term “aryl” relates to groups having the meaning of an aromaticring, e.g. phenyl, as well as to fused aromatic rings. Aryl contains onering with at least 6 carbon atoms or two rings with totally 10 carbonatoms and with alternating double (resonant) bonds between carbon atoms.The most freqently used aryls are e.g. phenyl or naphthyl. In general,aryl groups may be linked to the rest of the molecule by any availablecarbon atom via a direct bond or via a C₁–C₄ alkylene group such asmethylene or ethylene.

The term “heteroaryl” relates to groups having the meaning of aromaticand partially aromatic groups of a monocyclic or bicyclic ring with 4 to12 atoms, at least one of them being a hetero atom such as O, S or N,and the available nitrogen atom or carbon atom is the binding site ofthe group to the rest of the molecule either via a direct bond or via aC₁–C₄ alkylene group defined earlier. Examples of this type arethiophenyl, pyrrolyl, imidazolyl, pyridinyl, oxazolyl, thiazolyl,pyrazolyl, tetrazolyl, pirimidinyl, pyrazinyl, quinolinyl or triazinyl.

The term “heterocycle” relates to five-member or six-member, fullysaturated or partly unsaturated heterocyclic groups containing at leastone hetero atom such as O, S or N, and the available nitrogen atom orcarbon atom is the binding site of the group to the rest of the moleculeeither via a direct bond or via a C₁–C₄ alkylene group defined earlier.The most frequent examples are morpholinyl, piperidyl, piperazinyl,pyrrolidinyl, pirazinyl or imidazolyl.

The term “alkanoyl” group relates to straight chains of acyl group suchas formyl, acetyl or propanoyl.

The term “aroyl” group relates to aromatic acyl groups such as benzoyl.

The term “optionally substituted” alkyl relates to alkyl groups, whichmay be optionally additionally substituted with one, two, three or moresubstituents. Such substituents may be a halogen atom (preferablyfluorine or chlorine), hydroxy, C₁–C₄ alkoxy (preferably methoxy orethoxy), thiol, C₁–C₄ alkylthio (preferably methylthio or ethylthio),amino, N-(C₁–C₄) alkylamino (preferably N-methylamino or N-ethylamino),N,N-di(C₁–C₄-alkyl)-amino (preferably dimethylamino or diethylamino),sulfonyl, C₁–C₄ alkylsulfonyl (preferably methylsulfonyl orethylsulfonyl), sulfinyl, C₁–C₄ alkylsulfinyl (preferablymethylsulfinyl).

The term “optionally substituted” alkenyl relates to alkenyl groupsoptionally additionally substituted with one, two or three halogenatoms. Such substituents may be e.g. 2-chloroethenyl,1,2-dichloroethenyl or 2-bromo-propene-1-yl.

The term “optionally substituted” aryl, heteroaryl or heterocyclerelates to aryl, heteroaryl or heterocyclic groups which may beoptionally additionally substituted with one or two substituents. Thesubstituents may be halogen (preferably chlorine or fluorine), C₁–C₄alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy,C₁–C₄ alkoxy (preferably methoxy or ethoxy), thiol, C₁–C₄ alkylthio(preferably methylthio or ethylthio), amino, N-(C₁–C₄) alkylamino(preferably N-methylamino or N-ethylamino), N,N-di(C₁–C₄-alkyl)-amino(preferably N,N-dimethylamino or N,N-diethylamino), sulfonyl, C₁–C₄alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl,C₁–C₄ alkylsulfinyl (preferably methylsulfinyl).

When X has the meaning of NR^(a) and R^(a) has the meaning of aprotecting group, R^(a) relates to groups such as alkyl (preferablymethyl or ethyl), alkanoyl (preferably acetyl), alkoxycarbonyl(preferably methoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl(preferably benzyloxycarbonyl), aroyl (preferably benzoyl), arylalkyl(preferably benzyl), alkylsilyl (preferably trimethylsilyl) oralkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).

When R³ and R⁴ together with N have the meaning of heteroaryl orheterocycle, this means that such heteroaryls or heterocycles have atleast one carbon atom replaced by a nitrogen atom, through which thegroups are linked to the rest of the molecule. Examples of such groupsare morpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-ylor piperazine-1-yl.

The term “pharmaceutically suitable salts” relates to salts of thecompounds of the formula I and include e.g. salts with C₁–C₄alkylhalides (preferably methyl bromide, methyl chloride) (quaternaryammonium salts), with inorganic acids (hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric or sulfuric acids) or with organicacids (tartaric, acetic, citric, maleic, lactic, fumaric, benzoic,succinic, methane sulfonic or p-toluene sulfonic acids).

Some compounds of the formula I may form salts with organic or inorganicacids or bases and these are also included in the present invention.

Solvates (most frequently hydrates), which may be formed by compounds ofthe formula I or salts thereof, are also an object of the presentinvention.

Depending upon the nature of particular substituents, the compounds ofthe formula I may have geometric isomers and one or more chiral centresso that there can exist enantiomers or diastereoisomers. The presentinvention also relates to such isomers and mixtures thereof includingracemates.

The present invention also relates to all possible tautomeric forms ofparticular compounds of the formula I.

A further object of the present invention relates to the preparation ofcompounds of the formula I according to processes comprising

-   -   a) for compounds of the formula I, wherein R¹ is hydrogen, a        cyclization of compounds of the formula III:

-   -   b) for compounds of the formula I, wherein Q₁ has the meaning of        —O—, a reaction of alcohols of the formula IV:

-   -    with compounds of the formula V:

-   -    wherein L¹ has the meaning of a leaving group,    -   c) for compounds of the formula I, wherein Q₁ has the meaning of        —O—, —NH—, —S— or —C═C—,    -   a reaction of compounds of the formula IVa:

-   -    wherein L² has the meaning of a leaving group,    -    with compounds of the formula Va:

-   -   d) for compounds wherein Q₁ has the meaning of —O—, —NH— or —S—,        a reaction of compounds of the formula IVb:

-   -    with compounds of the formula V, wherein L¹ has the meaning of        a leaving group,    -   e) for compounds wherein Q₁ has a meaning of —C═C—, a reaction        of compounds of the formule IVb, wherein Q₁ has the meaning of        carbonyl, with phosphorous ylides.

Preparation methods:

a) Compounds of the formula I, wherein R¹ has the meaning of hydrogen,are obtained by reaction of the compounds of the formula III withNa₂S₂O₄ or Na₂SO₃; in an aqueous-alcoholic medium (preferablyethanol-water) under heating (preferably at boiling temperature) for 1to 5 hours (U.S. Pat. No. 4,267,190). The obtained crude product may bepurified by recrystallization or column chromatography.

The starting compounds for preparing compounds of the formula III arethe corresponding dibenzo-cycloheptanones of the formula IIIa:

and a compound of the formula IIIb:

The compounds of the formula IIIa and the compound of the formula IIIbare already known or are prepared by methods disclosed for thepreparation of analogous compounds.

Compounds of the formula III may be prepared in an alcoholic medium inthe presence of a corresponding alcoholate (preferably sodium ethoxidein ethanol) at elevated temperature (50° C. to 100° C.) during 1 to 5hours (Severin T, Poehlmann H, Chem. Ber. 1977, 110:491–499). Productsconsisting of a mixture of geometric isomers may be isolated andpurified by chromatography on silica gel column or may be converted tocorresponding pyrrol derivatives without isolation by cyclization.

b) Compounds of the formula I according to the present process may beprepared by reaction of alcohols of the formula IV and compounds of theformula V, wherein L¹ has the meaning of a leaving group, which may be ahalogen atom (most frequently bromine, iodine or chlorine) orsulfonyloxy group (most frequently trifluoromethylsulfonyloxy orp-toluenesulfonyloxy). The reaction of condensation may be carried outaccording to methods disclosed for the preparation of analogouscompounds (Menozzi G et al., J. Heterocyclic Chem., 1997, 34:963–968 orWO 01/87890). The reaction is carried out at a temperature from 20° C.to 100° C. during 1 to 24 hours in a two-phase system (preferably with50% NaOH/toluene) in the presence of a phase transfer catalyst(preferably benzyl triethyl ammonium chloride, benzyl triethyl ammoniumbromide, cetyl trimethyl bromide). After treating the reaction mixture,the products formed are isolated by recrystallization or chromatographyon a silica gel column.

The starting substances, alcohols of the formula IV, may be preparedfrom the compounds of the formula I, wherein R¹ has the meaning of asuitable functional group and R² has the meaning of a protecting group.Thus e.g. alcohols of the formula IV may be obtained by the reduction ofaldehyde, carboxyl of alkyloxycarbonyl group (e.g. methyloxycarbonyl orethyloxycarbonyl) by using metal hydrides such as lithium aluminumhydride or sodium borohydride. Further, alcohols of the formula IV maybe prepared by hydrolysis of the corresponding esters in an alkaline oracidic medium.

The starting compounds of the formula V are already known or areprepared according to methods disclosed for the preparation of analogouscompounds.

c) Compounds of the formula I according to the present process may beprepared by reacting compounds of the formula IVa, wherein L² has themeaning of a leaving group defined earlier for L¹, and compounds of theformula Va, wherein Q₁ has the meaning of oxygen, nitrogen, sulfur or—C≡C—. The most suitable condensation reactions are reactions ofnucleophilic substitution on a saturated carbon atom as disclosed in theliterature.

The starting compounds of the formula IVa (most frequently halogens) maybe obtained by halogenation (e.g. bromination of chlorination) of thecompounds of the formula IV with common halogenating agents (hydrobromicacid, PBr₃, SOCl₂ or PCl₅) by processes disclosed in the literature. Theobtained compounds may be isolated or may be used without isolation asappropriate intermediates for the preparation of the compounds of theformula I.

The starting compounds of the formula Va are already known or areprepared according to methods disclosed for the preparation of analogouscompounds.

d) The compounds of the formula I, wherein Q₁ has the meaning of —O—,—NH— or —S—, may be prepared by condensation of the compounds of theformula IVb and of compounds of the formula V, wherein L¹ has themeaning of a leaving group defined earlier. The reaction may be carriedout as disclosed in method b) or at reaction conditions for anucleophilic substitution disclosed in the literature. The startingalcohols, amines and thiols may be obtained by a reaction of water,ammonia or hydrogen sulfide with compounds IVa according to processesdisclosed in the literature.

e) The alcohols of the structure IV may be oxidized to correspondingcompounds of the formula IVb, wherein Q₁ has the meaning of carbonyl,which may further, by reaction with corresponding ylide reagents, resultin a prolongation of the chain and in the formation of an alkenylsubstituent with carbonyl or ester groups as disclosed in HR patentapplication No. 20000310.

Besides the reactions mentioned above, the compounds of the formula Imay be prepared by transforming other compounds of the formula I and itis to be understood that the present invention also comprises suchcompounds and processes. A special example of a change of a functionalgroup is the reaction of the aldehyde group with chosen phosphorousylides resulting in a prolongation of the chain and the formation of analkenyl substituent with carbonyl or ester groups as disclosed in HRpatent application No. 20000310. These reactions are carried out insolvents such as benzene, toluene or hexane at elevated temperature(most frequently at boiling temperature).

By reacting the compounds of the formula IVa with 1-alkyne in analkaline medium (such as sodium amide in ammonia), the compounds of theformula I, wherein Q₁ is —C≡C—, are obtained. The reaction conditions ofthis process are disclosed in the literature. At similar reactionconditions (nucleophilic substitution) various ether, thioether or aminederivatives may be prepared.

The formylation of the compounds of the formula I by processes such ase.g. Vilsmeier acylation (U.S. Pat. No. 4,267,184) or reaction of n-BuLiand NAN-dimethylformamide is a further general example of atransformation. The reaction conditions of these processes arewell-known in the literature.

By hydrolysis of the compounds of the formula I having nitrile, amide orester groups, there may be prepared compounds with a carboxyl group,which are suitable intermediates for the preparation of other compoundswith novel functional groups such as e.g. esters, amides, halides,anhydrides, alcohols or amines.

Oxidation or reduction reactions are a further possibility of the changeof substituents in the compounds of the formula I. Most frequently usedoxidation agents are peroxides (hydrogen peroxide, m-chloroperbenzoicacid or benzoyl peroxide) or permanganate, chromate or perchlorate ions.Thus e.g. by the oxidation of an alcohol group by pyridinyl dichromateor pyridinyl chlorochromate, an aldehyde group is formed, which groupmay be converted to a carboxyl group by further oxidation.

By a selective oxidation of alkylthio group, alkylsulfinyl oralkylsulfonyl groups may be prepared.

By the reduction of the compounds with a nitro group, the preparation ofamino compounds is made possible. The reaction is carried out underusual conditions of catalytic hydrogenation or electrochemically. Bycatalytic hydrogenation using palladium on carbon, alkenyl substituentsmay be converted to alkyl ones or nitrile group can be converted toaminoalkyl.

Various substituents of the aromatic structure in the compounds of theformula I may be introduced by standard substitution reactions or byusual changes of individual functional groups. Examples of suchreactions are aromatic substitutions, alkylations, halogenation,hydroxylation as well as oxidation or reduction of substituents.Reagents and reaction conditions are known from the literature. Thuse.g. by aromatic substitution a nitro group is introduced in thepresence of concentrated nitric acid and sulfuric acid. By using acylhalides or alkyl halides, the introduction of an acyl group or an alkylgroup is made possible. The reaction is carried out in the presence ofLewis acids such as aluminum- or iron-trichloride in conditions ofFriedel-Crafts reaction. By the reduction of the nitro group, an aminogroup is obtained, which is by the reaction of diazotizing converted toa suitable starting group, which may be replaced with one of thefollowing groups: H, CN, OH, Hal.

In order to prevent undesired interaction in chemical reactions, it isoften necessary to protect certain groups such as e.g. hydroxy, amino,thio or carboxy. For this purpose a great number of protecting groupsmay be used (Green TW, Wuts PGH, Protective Groups in Organic Synthesis,John Wiley and Sons, 1999) and the choice, use and elimination thereofare conventional methods in chemical synthesis.

A convenient protection for amino or alkylamino groups are groups suchas e.g. alkanoyl (acetyl), alkoxycarbonyl (methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl); arylmethoxycarbonyl(benzyloxycarbonyl), aroyl (benzoyl) or alkylsilyl (trimethylsilyl ortrimethylsilylethoxymethyl) groups. The conditions of removing aprotecting group depend upon the choice and the characteristics of thisgroup. Thus e.g. acyl groups such as alkanoyl, alkoxycarbonyl or aroylmay be eliminated by hydrolysis in the presence of a base (sodiumhydroxide or potassium hydroxide), tert-butoxycarbonyl or alkylsilyl(trimethylsilyl) may be eliminated by treatment with a suitable acid(hydrochloric, sulfuric, phosphoric or trifluoroacetic acid), whereasarylmethoxycarbonyl group (benzyloxycarbonyl) may be eliminated byhydrogenation using a catalyst such as palladium on carbon.

Salts of the compounds of the formula I may be prepared by generallyknown processes such as e.g. by reacting the compounds of the formula Iwith a corresponding base or acid in an appropriate solvent or solventmixture e.g. ethers (diethylether) or alcohols (ethanol, propanol orisopropanol).

Another object of the present invention concerns the use of the presentcompounds in the therapy of inflammatory diseases and conditions,especially all diseases and conditions induced by excessive TNF-α andIL-1 secretion.

Inhibitors of production of cytokins or inflammation mediators, whichare the object of the present invention, or pharmacologically acceptablesalts thereof may be used in production of drugs for the treatment andprophylaxis of any pathological condition or disease induced byexcessive unregulated production of cytokins or inflammation mediators,which drugs should contain an effective dose of said inhibitors.

The present invention specifically relates to an effective dose of TNF-αinhibitor, which may be determined by usual methods.

Further, the present invention relates to a pharmaceutical formulationcontaining an effective non-toxic dosis of the present compounds as wellas pharmaceutically acceptable carriers or solvents.

The preparation of pharmaceutical formulations may include blending,granulating, tabletting and dissolving ingredients. Chemical carriersmay be solid or liquid. Solid carriers may be lactose, sucrose, talcum,gelatine, agar, pectin, magnesium stearate, fatty acids etc. Liquidcarriers may be syrups, oils such as olive oil, sunflower oil or soyabean oil, water etc. Similarly, the carrier may also contain a componentfor a sustained release of the active component such as e.g. glycerylmonostearate or glyceryl distearate. Various forms of pharmaceuticalformulations may be used. Thus, if a solid carrier is used, these formsmay be tablets, hard gelatine capsules, powder or granules, which may beadministered in capsules per os. The amount of the solid carrier mayvary, but it is mainly from 25 mg to 1 g. If a liquid carrier is used,the formulation would be in the form of a syrup, emulsion, soft gelatinecapsules, sterile injectable liquids such as ampoules or non-aqueousliquid suspensions.

Compounds according to the present invention may be applied per os,parenterally, locally, intranasally, intrarectally and intravaginally.The parenteral route herein means intravenous, intramuscular andsubcutaneous applications. Appropriate formulations of the presentcompounds may be used in the prophylaxis as well as in the treatment ofinflammatory diseases and conditions induced by an excessive unregulatedproduction of cytokins or inflammation mediators, primarily TNF-α. Theycomprise e.g. rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis and other arthritic pathological conditions and diseases,eczemas, psoriasis and other inflammatory skin conditions, inflammatoryeye diseases, Crohn's disease, ulcerative colitis and asthma.

The inhibitory action of the present compounds upon TNF-α and IL-1secretion was determined by the following in vitro and in vivoexperiments:

Determination of TNF-α and IL-1 Secretion in Human Peripheral BloodMononuclear Cells in vitro

Human peripheral blood mononuclear cells (PBMC) were prepared fromheparinized whole blood after separating PBMC on Ficoll-Paque™ Plus(Amersham-Pharmacia). To determine the TNF-α level, 3.5–5×10⁴ cells werecultivated in a total volume of 200 μl for 18 to 24 hours on microtitreplates with a flat bottom (96 wells, Falcon) in RPMI 1640 medium, intowhich there were added 10% FBS (Fetal Bovine Serum, Biowhittaker)previously inactivated at 56° C./30 min, 100 units/ml of penicillin, 100mg/ml of streptomycin and 20 mM HEPES (GIBCO). The cells were incubatedat 37° C. in an atmosphere with 5% CO₂ and 90% humidity. In a negativecontrol the cells were cultivated only in the medium (NC), whereas in apositive control TNF-α secretion was triggered by adding 1 ng/ml oflipopolysaccharides (LPS, E. coli serotype 0111:B4, SIGMA) (PC). Theeffect of the tested substances upon TNF-α secretion was investigatedafter adding them into cultures of cells stimulated by LPS (TS). TheTNF-α level in the cell supernatant was determined by ELISA procedureaccording to the suggestions of the producer (R&D Systems). The testsensitivity was <3 pg/ml TNF-α. The IL-1 level was determined in anassay under the same conditions and with the same number of cells andthe same concentration of the stimulus by ELISA procedure (R&D Systems).The percentage of inhibition of TNF-α or IL-1 production was calculatedby the equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

The IC-50 value was defined as the substance concentration, at which 50%of TNF-α production were inhibited.

Compounds showing IC-50 with 20 μM or lower concentrations are active.

Determination of TNF-α and IL-1 Secretion in Mouse PeritonealMacrophages In Vitro

In order to obtain peritoneal macrophages, Balb/C mouse strain males,age 8 to 12 weeks, were injected i.p. with 300 μg of zymosan (SIGMA)dissolved in a phosphate buffer (PBS) in a total volume of 0.1 ml/mouse.After 24 hours the mice were euthanized according to the LaboratoryAnimal Welfare Act. The peritoneal cavity was washed with a sterilephysiological solution (5 ml). The obtained peritoneal macrophages werewashed twice with a sterile physiological solution and, after the lastcentrifugation (350 g/10 min), resuspended in RPMI 1640, into which 10%of FBS were added. In order to determine TNF-α secretion, 5×10⁴cells/well were cultivated in a total volume of 200 μl for 18 to 24hours on microtitre plates with a flat bottom (96 wells, Falcon) in RPMI1640 medium, into which 10% FBS (Fetal Bovine Serum, Biowhittaker)inactivated by heat, 100 units/ml of penicillin, 100 mg/ml ofstreptomycin, 20 mM HEPES and 50 μM 2-mercaptoethanol (all of GIBCO)were added. The cells were incubated at 37° C. in an atmosphere with 5%CO₂ and 90% humidity. In a negative control the cells were cultivatedonly in a medium (NC), whereas in a positive control the TNF-α secretionwas triggered by adding 10 ng/ml of lipopolysaccharides (LPS, E. coliserotype 0111:B4, SIGMA) (PC). The effect of the substances upon theTNF-α secretion was investigated after adding them into cultures ofcells stimulated with LPS (TS). The TNF-α level in the cell supernatantwas determined by ELISA procedure specific for TNF-α and IL-1 (R&DSystems, Biosource). The percentage of inhibition of TNF-α or IL-1production was calculated by the equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

The IC-50 value was defined as the substance concentration, at which 50%of TNF-α production were inhibited.

Compounds showing IC-50 with 10 μM or lower concentrations are active.

In vivo Model of LPS-Induced Excessive TNF-α or IL-1 Secretion in Mice

TNF-α or IL-1 secretion in mice was induced according to the alreadydisclosed method (Badger A M et al., J. Pharmac. Env. Therap., 1996,279:1453–1461). Balb/C males, age 8 to 12 weeks, in groups of 6 to 10animals were used. The animals were treated p.o. either with a solventonly (in negative and in positive controls) or with solutions ofsubstances 30 minutes prior to i.p. treatment with LPS (E. coli serotype0111:B4, Sigma) in a dosis of 1–25 μg/animal. Two hours later theanimals were euthanized by means of i.p. Roumpun (Bayer) and Ketanest(Parke-Davis) injection. A blood sample of each animal was taken into aVacutainer tube (Becton Dickinson) and the plasma was separatedaccording to the producer's instructions. The TNF-α level in the plasmawas determined by ELISA procedure (Biosource, R&D Systems) according tothe producer's instructions. The test sensitivity was <3 μg/ml TNF-α.The IL-1 level was determined by ELISA procedure (R&D Systems). Thepercentage of inhibition of TNF-α or IL-1 production was calculated bythe equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

Active are the compounds showing 30% or more inhibition of TNF-αproduction at a dosis of 10 mg/kg.

Writhing Assay for Analgetic Activity

In this assay pain is induced by the injection of an irritant, mostfrequently acetic acid, into the peritoneal cavity of mice. Animalsreact with characteristic writhings, which has given the name to theassay (Collier HOJ et al., Pharmac. Chemother., 1968, 32:295–310; FukawaK et al., J. Pharmacol. Meth., 1980, 4:251–259; Schweizer A et al.,Agents Actions, 1988, 23:29–31). The assay is convenient for thedetermination of analgetic activity of compounds. Procedure: male Balb/Cmice (Charles River, Italy), age 8 to 12 weeks, were used. A controlgroup received methyl cellulose p.o. 30 minutes prior to i.p.application of acetic acid in a concentration of 0.6%, whereas testgroups received standard (acetylsalicylic acid) or test substances inmethyl cellulose p.o. 30 minutes prior to i.p. application of 0.6%acetic acid (volume 0.1 ml/10 g). The mice were placed individuallyunder glass funnels and the number of writhings was registered for 20minutes for each animal. The percentage of writhing inhibition wascalculated according to the equation:% inhibition=(mean value of number of writhings in the controlgroup−number of writhings in the test group)/number of writhings in thecontrol group*100.

Active are the compounds showing such analgetic activity asacetylsalicylic acid or better.

In Vivo Model of LPS-Induced Shock in Mice

Male Balb/C mice (Charles River, Italy), age 8 to 12 weeks, were used.LPS isolated from Serrathie marcessans (Sigma, L-6136) was diluted insterile physiological solution. The first LPS injection was administeredintradermally in a dosis of 4 μg/mouse. 18 to 24 hours later, LPS wasadministered i.v. in a dosis of 90–200 μg/mouse. A control groupreceived two LPS injections as disclosed above. The test groups receivedsubstances p.o. half an hour prior to each LPS application. Survivalafter 24 hours was observed.

Active are the substances at which the survival at a dosis of 30 mg/kgwas 40% or more.

Compounds from Examples 5 to 7 show activity in at least twoinvestigated assays though these results only represent an illustrationof the biological activity of compounds and should not limit theinvention in any way.

EXAMPLE 1

-   a) 1H-8-Oxa-1-aza-dibenzo[e,h]azulene (4)

To an ethanolic solution of11-[2-(dimethyl-hydrazono)-ethylidene]-11H-dibenzo[b,f]oxepine-10-one(6.16 mmol in 47 mL), Na₂S₂O₄ (0.036 mol) and water (23 mL) were added.The reaction mixture was stirred under heating at boiling temperaturefor 3 to 4 hours. Then it was poured into an ice-water mixture and theproduct was extracted with dichloromethane. The crude product waspurified by column chromatography and an oily product was isolated.

-   b) 11-Chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene (5)

According to the above process starting from8-chloro-11-[2-(dimethyl-hydrazono)-ethylidene]-1H-dibenzo[b,f]oxepine-10-onea product in the form of an oil was obtained.

-   c) 1H-8-Thia-1-aza-dibenzo[e,h]azulene (6)

According to the above process, starting from11-[2-(dimethyl-hydrazono)-ethylidene]-11H-dibenzo[b,f]thiepine-10-onean oily product was obtained.

EXAMPLE 2

-   1H-8-Oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde (7)

To dimethylformamide (38.7 mmol) cooled to 0° C., phosphoric trichloride(25.7 mmol) was added drop by drop and then the reaction mixture wasstirred at room temperature for 15 minutes. To the reaction mixturecooled again to 0° C., a dimethylformamide solution of1H-8-oxa-1-aza-dibenzo[e,h]azulene (4, 2.57 mmol in 5 mL) was added.Then the reaction mixture was stirred at 70–80° C. for 1–2 hours, cooledto room temperature and, by adding 50% NaOH, the pH was adjusted to 8–9.Such alkaline solution was heated for 1 hour at 70° C., then cooled toroom temperature and poured into an ice-water mixture. The organicproduct was extracted with ethyl acetate, purified by chromatography onsilica gel column and a yellow oily product was isolated.

According to the above process, by formylation of the compounds 5 and 6there were prepared the compounds

-   11-chloro-1H-8-oxa-J-aza-dibenzo[e,h]azulene-2-carbaldehyde (8) and    1H-8-thia-1-aza-dibenzo[e,h]azulene-2-carbaldehyde (9).

EXAMPLE 3

-   1-(2-Trimethylsilyl-ethoxymethyl)-1H-8-oxa-J-aza-dibenzo[e,h]azulene-2-carbaldehyde    (10)

A tetrahydrofuran solution of1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde (7; 1.9 mmol in 15 mL)was cooled to 0° C. and slowly sodium hydride (60% dispersion in mineraloil, 125 mg) was added thereto. The reaction mixture was stirred at 0°C. until hydrogen stopped to develop (15–30 minutes) and trimethylsilylethoxymethyl chloride, (CH₃)₃SiCH₂CH₂OCH₂Cl (SEM-Cl; 2 mmol) was addedto the cooled reaction mixture. The reaction mixture was stirred at roomtemperature for one hour and then it was diluted by addition of water.The organic product was extracted with ethyl acetate. After drying theorganic extracts on anhydrous sodium sulfate and evaporating thesolvent, the crude product was purified by chromatography on a silicagel column. A dark oily product was isolated.

According to the above process, by silylating the compounds 8 and 9there were prepared the compounds

-   11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde (11)    and-   1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-carbaldehyde    (12).

EXAMPLE 4

-   [1-(2-Trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol    (13)

To a methanolic solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde(10; 2.45 mmol in 25 mL), NaBH₄ (4 mmol) was added and the reactionmixture was stirred at room temperature for 2 hours. Then the pH of thereaction mixture was adjusted to 5 by adding acetic acid, the solventwas evaporated to dryness and the dry residue was extracted with ethylacetate. By purifying the crude product by chromatography on a silicagel column an oily product was isolated.

According to the above process, by reacting the compounds 11 and 12 withNaBH₄ there were prepared the compounds

-   [11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol (14)    and-   [1-(2-trimethylsilyl-ethoxymethyl)-J    H-8-thia-1-aza-dibenzo[e,h]azulene-2-yl]-methanol (15).

TABLE 1 I

cmp. X Y Z R¹ R² MS(m/z) ¹H NMR(ppm, CDCl₃) 4 O H H H H 231.9[M − H]⁻6.59(t, 1H); 6.97(t, 1H); 7.15–7.49(m, 8H); 8.48(bs, 1H) 5 O H 11-Cl H H2.66[M − H]⁻ 6.58(t, 1H); 6.97(t, 1H); 7.16–7.25(m, 6H); 7.47(m, 1H);8.49(bs, 1H) 6 S H H H H 250[MH]⁺ 6.61(t, 1H); 6.99(t, 1H); 7.20–7.65(m,8H); 8.54(bs, 1H) 7 O H H CHO H 262.2[MH]⁺ 7.19–7.52(m, 9H); 9.83(s, 1H)8 O H 11-Cl CHO H 353 — [M + Na⁺ + MeOH] 9 S H H CHO H 298[M + Na⁺]7.27–7.69(m, 8H); 8.04(bs, 1H); 9.67(s, 1H) 10 O H H CHO SEM^(a)414.1[M + Na⁺] 0.03(s, 9H); 0.99(m, 2H); 3.83(m, 2H); 5.38(s, 2H);7.23–7.53(m, 8H); 8.02(m, 1H); 9.74(s, 1H) 11 O H 11-Cl CHO SEM448.4[M + Na⁺] 0.024(s, 9H); 0.92–1.09(m, 2H); 3.50–3.99(m, 2H); 5.37(s,2H); 7.20–8.07(m, 8H); 9.74(s, 1H) 12 S H H CHO SEM 430.1[M + Na⁺]0.02(s, 9H); 0.93(t, 2H); 3.55–3.75(dm, 2H); 5.53(d, 1H); 5.93(d, 1H);7.27–7.8(m, 9H); 10.04(s, 1H) 13 O H H CH₂OH SEM 393.2[MH]⁺ 0.025(s,9H); 0.97(t, 2H); 1.59(bs, 1H); 3.64(m, 2H); 4.79(s, 2H); 5.48(s, 2H);6.6(s, 1H); 7.19–7.52(m, 8H) 14 O H 11-Cl CH₂OH SEM 450 0.04(s, 9H);1.07(m, 2H); 1.57(s, 1H); 3.69(m, 2H); 4.77(s, 2H); 5.39(s, 2H); [M +Na⁺]; 6.56(s, 1H); 7.18–7.31(m, 5H); 7.46(m, 1H); 7.55(d, 1H) 410 [M −OH] 15 S H H CH₂OH SEM 432.1[M + Na⁺]; 0.02(s, 9H); 0.93(m, 2H); 1.6(bs,1H); 3.33–3.62(dm, 2H); 4.82(s, 2H); 392.1[M − OH] 5.47(s, 2H); 6.61(s,1H); 7.23–7.74(m, 8H) ^(a)SEM = (CH₃)₃SiCH₂CH₂OCH₂

EXAMPLE 5 a)Dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethox]-ethyl}-amine(I; X═O, Y═Z═H, R¹═(CH₃)₂N(CH₂)₂OCH₂, R²═(CH₃)₃Si(CH₂)2OCH₂)Dimethyl-[2-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine(I; X═O, Y═Z═H, R¹═(CH₃)₂N(CH₂)₂OCH₂, R²═H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (5.2 mmol)in 50% sodium hydroxide (10 mL), benzyl triethyl amrnmonium chloride (acatalytic amount) and a solution of the alcohol 13 (0.3 mmol) in toluene(15 mL) were added. The reaction mixture was heated under vigorousstirring at boiling temperature for 3 hours. Then it was cooled to roomtemperature, diluted with water and extracted with dichloromethane. Theorganic extract was washed with water, dried on anhydrous Na₂SO₄ andevaporated under reduced pressure. After purifying the evaporatedresidue by chromatography on a silica gel column,dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-aminewas isolated in the form of an oil;

MS (m/z): 465.4 [MH]⁺.

To a solution of the silyl compound prepared above (0.11 mmol) intetrahydrofuran (1 mL) tetrabutylammonium fluoride (5 mmol, 1M solutionin THF) was added. The reaction mixture was heated for 5 hours atboiling temperature and then it was cooled to room temperature, dilutedwith diethyl ether and washed with water. The organic extracts weredried on anhydrous Na₂SO₄, the solvent was evaporated under reducedpressure and the crude product was purified by chromatography on asilica gel column. After purifying a light yellow oilydimethyl-[2-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-aminewas isolated; MS (m/z): 357.4 [M+Na⁺].

b)Dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-amine(I; X═O, Y═Z═H, R²═(CH₃)₂N(CH₂)₃OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)Dimethyl-[3-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine(I; X═O, Y═Z═H, R¹═(CH₃)₂N(CH₂)₃OCH₂, R²═H)

By a reaction of the alcohol 13 (0.3 mmol) and 3-dimethylaminopropylchloride hydrochloride (4.7 mmol),dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy-propyl}-aminewas obtained according to the process disclosed in Example 5a in theform of a light yellow oily product.

MS (m/z): 479.4 [MH]⁺.

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by chromatography on asilica gel column,dimethyl-[3-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-aminein the form of a light yellow oily product was obtained;

MS (m/z): 349.4 [MH]⁺.

EXAMPLE 6 a) {2-[11-Chloro-1-(2-trimethylsilyl-ethoxymethyl)-]H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy-ethyl}-dimethyl-amine (1;X═O, Y═H, Z=11-Cl, R¹═(CH₃)₂N(CH₂)₂OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)[2-(11-Chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine(I; X═O, Y═H, Z=11-Cl, R¹═(CH₃)₂N(CH₂)₂OCH₂, R²═H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (5.2 mmol)in 50% sodium hydroxide (10 mL), benzyltriethyl ammonium chloride (acatalytic amount) and a solution of the alcohol 14 (0.28 mmol) intoluene (10 mL) were added. The reaction mixture was heated undervigorous stirring at boiling temperature for 4 hours. Then it was cooledto room temperature, diluted with water and extracted withdichloromethane. The organic extract was washed with water, dried onanhydrous Na₂SO₄ and evaporated under reduced pressure. After purifyingthe evaporated residue,{2-[11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-dimethyl-aminewas isolated by chromatography on silica gel column in the form of anoily product;

MS (m/z): 499.2 (MH⁺).

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by columnchromatography,[2-(11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-aminein the form of a light yellow oil was obtained;

MS (m/z): 369.2 [MH]⁺.

b){3-[J1-Chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl)-dimethyl-amine(I; X═O, Y═H, Z=11-Cl, R¹═(CH₃)₂N(CH₂)₃OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)[3-(11-Chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine(I; X═O, Y═H, Z=11-Cl, R¹═(CH₃)₂N(CH₂)₃OCH₂, R²═H)

By reacting the alcohol 14 (0.28 mmol) and 3-dimethylaminopropylchloride hydrochloride (4.7 mmol) according to the process disclosed inExample 5a,(3-[f]-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-dimethyl-aminein the form of a light oily product was obtained;

MS (m/z): 513.2 [MH]⁺.

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by chromatography on asilica gel column,[3-(11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-aminein the form of a light oil was obtained;

MS (m/z): 383.2 [MH]⁺.

EXAMPLE 7 a)Dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-amine(I, X═S, Y═Z═H, ═(CH₃)₂N(CH₂)₂OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)Dimethyl-[2-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine(I; X═S, Y═Z═H, R¹═(CH₃)₂N(CH₂)2OCH₂, R²═H)

To a solution of 2-dimethylaminoethyl chloride hydrochloride (5.2 mmol)in 50% sodium hydroxide (10 mL), benzyltriethyl ammonium chloride (acatalytic amount) and a solution of the alcohol 15 (0.39 mmol) intoluene (15 mL) were added. The reaction mixture was heated undervigorous stirring at boiling temperature for 4 hours. Then it was cooledto room temperature, diluted with water and extracted withdichloromethane. The organic extract was washed with water, dried onanhydrous Na₂SO₄ and evaporated under reduced pressure. After purifyingthe evaporated residue,dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-aminewas isolated by chromatography on a silica gel column in the form of anoil;

MS (m/z): 480.9 [MH]⁺.

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by chromatography on asilica gel column,dimethyl-[2-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-aminewas obtained in the form of an oil;

¹H NMR (ppm, CDCl₃): 2.39 (s, 6H); 2.72 (m, 2H); 3.74 (m, 2H); 4.70 (s,2H); 6.42 (s, 1H); 7.18–7.61 (m, 8H); 11.06 (s, 1H);

MS (m/z): 351.1 [MH]⁺.

b)Dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-amine(I, X═S, Y═Z═H, R¹═(CH₃)₂N(CH₂)₃OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)Dimethyl-[3-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine(I; X═S, Y═Z═H, R¹═(CH₃)₂N(CH)₃OCH₂, R²═H)

By reacting the alcohol 15 (0.39 mmol) and 3-dimethylaminopropylchloride hydrochloride (4.7 mmol) according to the process disclosed inExample 5a,dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-aminewas obtained in the form of an oil;

¹H NMR (ppm, CDCl₃): 0.049 (s, 9H); 0.87 (m, 2H); 1.96–2.04 (m, 2H);2.47 (s, 6H); 2.67 (m, 2H); 3.27–3.58 (dm, 2H); 3.67 (m, 2H); 4.73 (m,2H); 5.47 (m, 2H); 6.59 (s, 1H); 7.24–7.75 (m, 8H);

MS (m/z): 495.2 [MH]⁺.

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by chromatography on asilica gel column,dimethyl-[3-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-aminewas obtained in the form of an oil;

¹H NMR (ppm, CDCl₃): 1.78–1.86 (m, 2H); 2.23 (s, 6H); 2.45 (t, 2H); 3.62(t, 2H); 4.63 (s, 2H); 6.45 (s, 1H); 7.18–7.62 (m, 8H); 9.8 (s, 1H);

MS (m/z): 365.1 [MH]⁺.

c)3-[1-(2-Trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine(I, X═S, Y═Z═H, R¹═H₂N(CH₂)₃OCH₂, R²═(CH₃)₃Si(CH₂)₂OCH₂)3-(1H-8-Thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine (1; X═S,Y═Z═H, R¹═H₂N(CH₂)₃OCH₂, R²═H)

By reacting the alcohol 15 (0.39 mmol) and 3-aminopropyl chloridehydrochloride (5.8 mmol) according to the process disclosed in Example5a,3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propylaminewas obtained in the form of an oil;

MS (m/z): 466.9 [MH]⁺.

After the removal of the N-protecting group according to the processdisclosed in Example 5a and purifying the product by chromatography on asilica gel column,3-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine wasobtained in the form of an oil;

MS (m/z): 336[MH]⁺; 335 [M−H]⁻.

Preparation of Starting compounds11-[2-(dimethyl-hydrazono)-ethylidene]-11H-dibenzo[b,f]oxepine-10-one(1)

A mixture of 11H-dibenzo[b,f]oxepine-10-one (9.52 mmol) andglyoxal-mono(dimethylhydrazone) (9.52 mmol) was dissolved in ethanol (25mL) and to the solution a freshly prepared ethanolic solution of sodiumethoxide (9.52 mmol Na in 25 mL of ethanol) was added drop by drop. Thereaction mixture was stirred under heating at boiling temperature for 2to 3 hours, then cooled to room temperature and poured to an ice-watermixture. Then the organic product was extracted with ethyl acetate, theorganic extracts were dried on anhydrous Na₂SO₄ and, after evaporatingthe solvent, the crude product was purified by chromatography on asilica gel column. An oily brown product (a mixture of configurationisomers) was isolated;

MS (m/z): 293 [MH]⁺.

Starting from 8-chloro-11H-dibenzo[b,f]oxepine-10-one there was formed8-chloro-11-[2-(dimethyl-hydrazono)-ethylidene]-11H-dibenzo[b,f]oxepine-10-one(2), which was obtained in the form of an oil;

MS (m/z): 349.1 [M+Na⁺].

Starting from 11H-dibenzo[b,f]thiepine-10-one there was formed11-[2-(dimethyl-hydrazono)-ethylidene]-11H-dibenzo[b,f]thiepine-10-one(3) in the form of an oil;

MS (m/z): 331 [M+Na⁺].

1. Compound of the formula I:

wherein X is O, S, S(═O), or S(═O2); Y and Z are each independentlyselected from the group consisting of hydrogen, halogen, C₁–C₄ alkyl,C₂–C₄ alkenyl, C₂–C₄alkynyl, halo-C₁–C₄alkyl, hydroxy, C₁–C₄ alkoxy,trifluoromethoxy, C₁–C₄alkanoyl, amino, amino-C₁–C₄alkyl,C₁–C₄alkylamino, N-(C₁–C₄-alkyl)amino, N,N-di(C₁–C₄-alkyl)amino, thiol,C₁–C₄alkylthio, sulfonyl, C₁–C₄ alkylsulfonyl, sulfinyl,C₁–C₄alkylsulfinyl, carboxy, C₁–C₄alkoxycarbonyl, cyano, and nitro; R¹is selected from the group consisting of hydrogen, halogen, anoptionally substituted C₁–C₇alkyl or C₂–C₇ alkenyl, C₂–C₇ alkynyl, anoptionally substituted aryl or heteroaryl, a heterocycle, hydroxy,hydroxy-C₂–C₇ alkenyl, hydroxy-C₂–C₇ alkynyl, C₁–C₇ alkoxy, thiol,thio-C₂–C₇ alkenyl, thio-C₂–C₇ alkynyl, C₁–C₇ alkylthio, amino,N-(C₁–C₇)alkylamino, N,N-di(C₁–C₇-alkyl)amino, (C₁–C₇-alkyl)amino,amino-C₂–C₇ alkenyl, amino-C₂–C₇ alkynyl, amino-C₁–C₇ alkoxy, C₁–C₇alkanoyl, aroyl, oxo-C₁–C₇ alkyl, C₁–C₇ alkanoyloxy, carboxy, anoptionally substituted C₁–₇ alkyloxycarbonyl or aryloxycarbonyl,carbamoyl, N-(C₁–C₇-alkyl)carbamoyl, N,N-di(C₁-C₇-alkyl)carbamoyl,cyano, cyano-C₁–C₇ alkyl, sulfonyl, C₁–C₇ alkylsulfonyl, sulfinyl, C₁–C₇alkylsulfinyl, nitro, and a substituent of the formula II:

wherein R³ and R⁴ an each independently selected from the groupconsisting of hydrogen, C₁–C₄alkyl, aryl or together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle or heteroaryl; m and n are each an integer from 0 to 3; Q₁and Q₂ are each independently selected from the group consisting ofoxygen, sulfur, and the groups

wherein y₁ and y₂ are each independently selected from the groupconsisting of hydrogen, halogen, an optionally substituted C₁–C₄alkyl oraryl, hydroxy, C₁C₄ alkoxy, C₁–C₄alkanoyl, thiol, C₁–C₄ alkylthio,sulfonyl, C₁–C₄alkylsulfonyl, sulfinyl, C₁–C₄ alkylsulfinyl, cyano, andnitro or y₁ and y₂ taken together with the carbon atom to which they areattached form a carbonyl or imino group; R² is selected from the groupconsisting of hydrogen, optionally substituted C₁–C₇ alkyl or aryl, anda protecting group selected from the group consisting of formyl, C₁–₇alkanoyl, C₁–C₇ alkoxycarbonyl, arylalkyloxycarbonyl, aroyl, arylalkyl,C₁–C₇ alkylsilyl, and C₁–C₇ alkylsilyl-alkoxy-alkyl; andpharmaceutically acceptable salts and solvates thereof.
 2. The compoundof claim 1, wherein X is S or O.
 3. The compound of claim 2, wherein Yis H and Z is H or Cl.
 4. The compound of claim 3, wherein R¹ is H, CHO,or CH₂OH, and R² is H or (CH₃)₃Si(CH₂)₂OCH₂.
 5. The compound of claim 3,wherein R¹ is


6. The compound of claim 5, wherein m is 1, Q₁ is O, n is 1 or 2, Q₂ isCH₂, R² is H or (CH₃)₃Si(CH₂)₂OCH₂, and R³ and R⁴ are each independentlyH or CH₃.
 7. The compound of claim 4 selected from the group consistingof: 1H-8-oxa-1-aza-dibenzo[e,h]azulene;11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene;1H-8-thia-1-aza-dibenzo[e,h]azulene;1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;1H-8-thia-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2carbaldehyde;1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-carbaldehyde;[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol;[11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-yl]-methanol;and[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-yl]-methanol.8. The compound of claim 6 selected from the group consisting of:dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-amine;dimethyl-[2-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine;dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-amine;dimethyl-[3-(1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine;{2-[11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-dimethyl-amine;[2-11-chloro-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine;{3-[11-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-dimethyl-amine;[3-(11-chloro-IH-8-oxa-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine;dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-amine;dimethyl-[2-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine;dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-amine;dimethyl-[3-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-amine;3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy]-propylamine;3-(1H-8-thia-1-aza-dibenzo[e,h]azulene-2-ylmethoxy)-propylamine; andpharmaceutically acceptable salts thereof.
 9. Process for thepreparation of a compound of the formula I:

wherein X is O, S, S(═O), or S(═O)2; Y and Z are each independentlyselected from the group consisting of hydrogen, halogen, C₁–₄ alkyl,C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo-C₁–C₄ alkyl, hydroxy, C₁–C₄ alkoxy,trifluoromethoxy, C₁–C₄ alkanoyl, amino, amino-C₁–C₄ alkyl, C₁–C₄alkylamino, N-(C₁–C₄-alkyl)amino, N,N-di(C₁–C₄-alkyl)amino, thiol, C₁–C₄alkylthio, sulfonyl, C₁–C₄ alkylsulfonyl, sulfinyl, C₁–C₄ alkylsulfinyl,carboxy, C₁–C₄ alkoxycarbonyl, cyano, nitro; R¹ may be hydrogen,halogen, an optionally substituted C₁–C₇ alkyl or C₂–C₇ alkenyl, C₂–C₇alkinyl, an optionally substituted aryl or heteroaryl and a heterocycle,hydroxy, hydroxy-C₂–C₇ alkenyl, hydroxy-C₂–C₇ alkinyl, C₁–C₇ alkoxy,thiol, thio-C₂–C₇ alkenyl, thio-C₂–C₇ alkinyl, C₁–C₇ alkylthio, amino,N-(C₁–C₇)alkylamino, N,N-di(C₁–C₇-alkyl)amino, (C₁–C₇-alkyl)amino,amino-C₂–C₇ alkenyl, amino-C₂–C₇ alkinyl, amino-C₁–C₇ alkoxy, C₁–C₇alkanoyl, aroyl, oxo-C₁–C₇ alkyl, C₁–C₇ alkanoyloxy, carboxy, anoptionally substituted C₁–C₇ alkyloxycarbonyl or aryloxycarbonyl,carbamoyl, N-(C₁–C₇-alkyl)carbamoyl, N,N-di(C₁–C₇-alkyl)carbamoyl,cyano, cyano-C₁–C₇ alkyl, sulfonyl, C₁–C₇ alkylsulfonyl, sulfinyl, C₁–C₇alkylsulfinyl, nitro, or a substituent of the formula II:

wherein R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, C₁–C₄ alkyl, aryl or, together with the nitrogenatom to which they are attached, form an optionally substitutedheterocycle or heteroaryl; m and n represent an integer from 0 to 3; Q₁and Q₂ are each independently selected from the group consisting ofoxygen, sulfur or groups:

wherein the substituents y₁, and y₂ are each independently selected fromthe group consisting of hydrogen, halogen, an optionally substitutedC₁–C₄ alkyl or aryl, hydroxy, C₁–C₄ alkoxy, C₁–C₄ alkanoyl, thiol, C₁–C₄alkylthio, sulfonyl, C₁–C₄ alkylsulfonyl, sulfinyl, C₁–C₄ alkylsulfinyl,cyano, nitro or y₁ and y₂ taken together with the carbon atom to whichthey are attached form a carbonyl or imino group; R² is selected fromthe group consisting of hydrogen, optionally substituted C₁–C₇alkyl oraryl, and a protecting group selected from the group consisting of:formyl, C₁–C₇ alkanoyl, C₁–C₇ alkoxycarbonyl, arylalkyloxycarbonyl,aroyl, arylalkyl, C₁–C₇ alkylsilyl, and C₁–C₇ alkylsilyl-alkoxy-alkyl;and pharmacologically acceptable salts and solvates thereof, the processcomprising: a) for compounds of the formula I wherein R¹ is hydrogen, acyclization of a compound of the formula III:

b) for compounds of the formula I, wherein Q₁ is —O—, a reaction of analcohol of the formula IV:

 with a compound of the formula V:

 wherein L¹ is a leaving group, c) for compounds of the formula I,wherein Q₁ is —O——NH—, —S— or —C≡C—, a reaction of a compound of theformula IVa:

 wherein L² is a leaving group, with a compound of the formula Va:

d) for compounds wherein Q₁ is —O—,—NH— or —S—, a reaction of a compoundof the formula IVb:

 with a compound of the formula V, wherein L¹ is a leaving group, e) forcompounds wherein Q₁ is —C═C—, a reaction of compound of the formulaIVb, wherein Q₁ is carbonyl, with phosphorous ylides.
 10. A method fortreating inflammation associated with TNF-α comprising administering toa subject in need of treatment an effective amount of a compoundaccording to claim
 5. 11. The compound of claim 1, and pharmaceuticallyacceptable salts and solvates thereof, wherein R² is(CH₃)₃Si(CH₂)₂OCH_(2.)
 12. The process of claim 9, wherein R² is(CH₃)₃Si(CH₂)₂OCH_(2.)